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  • CLASSES

    Small Molecule Antineoplastic Mesenchymal-Epithelial Transition (MET) Inhibitors

    DEA CLASS

    Rx

    DESCRIPTION

    Kinase inhibitor targeting mesenchymal-epithelial transition (MET)
    Used for metastatic non-small cell lung cancer (NSCLC) in patients whose tumors have a mutation that leads to MET exon 14 skipping
    May cause photosensitivity; patients should limit exposure to ultraviolet light and wear sunscreen or protective clothing during treatment

    COMMON BRAND NAMES

    TABRECTA

    HOW SUPPLIED

    Capmatinib/TABRECTA Oral Tab: 150mg, 200mg

    DOSAGE & INDICATIONS

    For the treatment of non-small cell lung cancer (NSCLC).
    NOTE: Capmatinib is designated by the FDA as an orphan drug for this indication.
    For the treatment of metastatic non-small cell lung cancer (NSCLC) in patients whose tumors have a mutation that leads to mesenchymal-epithelial transition (MET) exon 14 skipping.
    NOTE: Patients should be selected based on the presence of a mutation that leads to MET exon 14 skipping in tumor or plasma specimens. If a mutation that leads to MET exon 14 skipping is not detected in a plasma specimen, test tumor tissue if feasible. Information on FDA-approved tests is available at www.fda.gov/CompanionDiagnostics.
    Oral dosage
    Adults

    400 mg PO twice daily until disease progression or unacceptable toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. In patients with NSCLC and a mutation leading to MET exon 14 skipping, EGFR wild-type and ALK negative status, and at least one measurable lesion, treatment with capmatinib resulted in an overall response rate (ORR) of 68% (complete response [CR], 4%) in patients who were treatment-naive (n = 28) for a median duration of 12.6 months in a multicenter, noncomparative trial (the GEOMETRY mono-1 study); the response lasted for 12 months or longer in 47% of patients. The ORR was 41% (CR, ,0%) for a median duration of 9.7 months in patients with previously-treated disease (n = 69); the response lasted for 12 months or longer in 32% of patients.

    MAXIMUM DOSAGE

    Adults

    400 mg PO twice daily.

    Geriatric

    400 mg PO twice daily.

    Adolescents

    Safety and effectiveness have not been established.

    Children

    Safety and effectiveness have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Baseline Hepatic Impairment
    Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
     
    Treatment-Related Hepatotoxicity
    Increased ALT and/or AST without increased total bilirubin
    Grade 3: Hold capmatinib therapy. If ALT/AST recovers to baseline within 7 days, resume capmatinib treatment at the same dose. If resolution occurs after 7 days, resume capmatinib treatment at a reduced dose.
    Grade 4: Permanently discontinue capmatinib therapy.
     
    Increased ALT and/or AST with increased total bilirubin (in the absence of cholestasis or hemolysis)
    AST/ALT greater than 3 times the upper limit of normal (ULN) with total bilirubin greater than 2 times ULN: Permanently discontinue capmatinib therapy.
     
    Increased total bilirubin without a concurrent increase in ALT and/or AST
    Grade 2: Hold capmatinib therapy. If bilirubin recovers to baseline within 7 days, resume capmatinib treatment at the same dose. If resolution occurs after 7 days, resume capmatinib treatment at a reduced dose.
    Grade 3: Hold capmatinib therapy. If bilirubin recovers to baseline within 7 days, resume capmatinib treatment at a reduced dose. If resolution occurs after 7 days, permanently discontinue capmatinib therapy.
    Grade 4: Permanently discontinue capmatinib therapy.

    Renal Impairment

    Mild or moderate renal impairment (CrCl 30 to 89 mL/min): No dose adjustment is recommended.
    Severe renal impairment (CrCl 15 to 29 mL/min): Capmatinib has not been studied in this population.

    ADMINISTRATION

    Oral Administration

    Capmatinib may be taken with or without food.
    Swallow tablets whole; do not break, crush, or chew the tablet.
    If a dose is missed or the patient vomits, the next dose should be taken at the regularly scheduled time; do not take an additional dose.

    STORAGE

    TABRECTA:
    - Protect from moisture
    - Store and dispense in original container
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Chronic lung disease (CLD), pneumonitis

    Use capmatinib with caution in patients who have a history of chronic lung disease (CLD); severe pneumonitis/interstitial lung disease (ILD) has been reported in patients treated with capmatinib. Advise patients to immediately report any new or worsening respiratory symptoms including fever, cough, or dyspnea. Monitor patients for new or worsening pulmonary symptoms indicative of ILD/pneumonitis and exclude other causes. Immediately withhold capmatinib in patients with suspected ILD/pneumonitis, and permanently discontinue treatment if no other potential causes are identified.

    Hepatic disease, hepatotoxicity

    Use capmatinib with caution in patients with pre-existing hepatic disease; hepatotoxicity has been reported in patients treated with capmatinib. Monitor liver function tests (ALT, AST, and bilirubin) at baseline, every 2 weeks during the first 3 months of therapy, and then once monthly or as clinically indicated; monitor more frequently in patients who develop increased transaminases or bilirubin. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for patients with elevated liver function tests.

    Skin photosensitivity disorder

    Based on animal studies, patients treated with capmatinib are at risk for a skin photosensitivity disorder. Advise patients to limit direct ultraviolet exposure and use sunscreen or wear protective clothing that is effective against ultraviolet light exposure during treatment with capmatinib.

    Pregnancy

    Pregnancy should be avoided by females of reproductive potential during capmatinib treatment and for at least 1 week after the last dose. Although there are no adequately controlled studies in pregnant women, capmatinib can cause fetal harm or death when administered during pregnancy based on its mechanism of action and animal studies. Women who are pregnant or who become pregnant while receiving capmatinib should be apprised of the potential hazard to the fetus. In rats, maternal toxicity (reduced weight gain and food consumption) occurred at approximately 1.4 times the human exposure at the recommended dose based on AUC. There were no maternal effects in rabbits at exposures of approximately 1.5 times the human exposure at the recommended dose based on AUC. At exposures of approximately 0.6 times the human exposure at the recommended dose based on AUC in rats, fetal effects included reduced weight, irregular/incomplete ossification, and increased fetal malformations (e.g., abnormal flexure/inward malrotation of hindpaws/forepaws, thinness of forelimbs, lack of or reduced flexion at the humerus/ulna joints, and narrowed or small tongue). These fetal effects were seen at much lower exposures in rabbits (approximately 0.016 times the human exposure based on AUC at the recommended dose).

    Contraception requirements, male-mediated teratogenicity, pregnancy testing, reproductive risk

    Counsel patients about the reproductive risk and contraception requirements during capmatinib treatment. Capmatinib can be teratogenic if taken by the mother during pregnancy. Females of reproductive potential should avoid pregnancy and use effective contraception during and for at least 1 week after treatment with capmatinib. Due to the risk of male-mediated teratogenicity, males with female partners of reproductive potential should also use effective contraception during treatment and for at least 1 week after the last dose. Females of reproductive potential should undergo pregnancy testing prior to initiation of capmatinib. Women who become pregnant while receiving capmatinib should be apprised of the potential hazard to the fetus.

    Breast-feeding

    Due to the potential for serious adverse reactions in nursing infants from capmatinib, advise women to discontinue breast-feeding during treatment and for 1 week after the final dose. It is not known whether capmatinib is present in human milk, although many drugs are excreted in human milk.

    ADVERSE REACTIONS

    Severe

    pancreatitis / Delayed / 0-10.0
    renal failure (unspecified) / Delayed / 0-10.0
    peripheral edema / Delayed / 9.0-9.0
    elevated hepatic enzymes / Delayed / 0.3-8.0
    fatigue / Early / 8.0-8.0
    dyspnea / Early / 7.0-7.0
    infection / Delayed / 4.8-4.8
    hyperamylasemia / Delayed / 4.4-4.4
    pleural effusion / Delayed / 3.6-3.6
    nausea / Early / 2.7-2.7
    vomiting / Early / 2.4-2.4
    pneumonitis / Delayed / 2.1-2.1
    interstitial lung disease / Delayed / 2.1-2.1
    chest pain (unspecified) / Early / 2.1-2.1
    hypoalbuminemia / Delayed / 1.8-1.8
    constipation / Delayed / 0.9-0.9
    anorexia / Delayed / 0.9-0.9
    back pain / Delayed / 0.9-0.9
    cough / Delayed / 0.6-0.6
    weight loss / Delayed / 0.6-0.6
    fever / Early / 0.6-0.6
    diarrhea / Early / 0.3-0.3
    hepatotoxicity / Delayed / Incidence not known
    hyperkalemia / Delayed / Incidence not known

    Moderate

    hyperbilirubinemia / Delayed / 2.0
    hyponatremia / Delayed / Incidence not known
    hypophosphatemia / Delayed / Incidence not known
    hypoglycemia / Early / Incidence not known
    leukopenia / Delayed / Incidence not known
    lymphopenia / Delayed / Incidence not known
    anemia / Delayed / Incidence not known

    Mild

    urticaria / Rapid / 0-10.0
    pruritus / Rapid / 0-10.0
    asthenia / Delayed / Incidence not known

    DRUG INTERACTIONS

    Abacavir; Dolutegravir; Lamivudine: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with capmatinib. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a P-glycoprotein (P-gp) substrate and capmatinib is a P-gp inhibitor.
    Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) Reduction or limitation of the caffeine dosage in medications or caffeine in beverages and food may be necessary during concurrent capmatinib therapy. Monitor for an increase in caffeine-related adverse reactions if coadministration with capmatinib is necessary. Caffeine is a sensitive CYP1A2 substrate and capmatinib is a weak CYP1A2 inhibitor. Coadministration with capmatinib increased caffeine exposure by 134%.
    Acetaminophen; Caffeine: (Moderate) Reduction or limitation of the caffeine dosage in medications or caffeine in beverages and food may be necessary during concurrent capmatinib therapy. Monitor for an increase in caffeine-related adverse reactions if coadministration with capmatinib is necessary. Caffeine is a sensitive CYP1A2 substrate and capmatinib is a weak CYP1A2 inhibitor. Coadministration with capmatinib increased caffeine exposure by 134%.
    Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Reduction or limitation of the caffeine dosage in medications or caffeine in beverages and food may be necessary during concurrent capmatinib therapy. Monitor for an increase in caffeine-related adverse reactions if coadministration with capmatinib is necessary. Caffeine is a sensitive CYP1A2 substrate and capmatinib is a weak CYP1A2 inhibitor. Coadministration with capmatinib increased caffeine exposure by 134%.
    Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: (Moderate) Reduction or limitation of the caffeine dosage in medications or caffeine in beverages and food may be necessary during concurrent capmatinib therapy. Monitor for an increase in caffeine-related adverse reactions if coadministration with capmatinib is necessary. Caffeine is a sensitive CYP1A2 substrate and capmatinib is a weak CYP1A2 inhibitor. Coadministration with capmatinib increased caffeine exposure by 134%.
    Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide: (Moderate) Reduction or limitation of the caffeine dosage in medications or caffeine in beverages and food may be necessary during concurrent capmatinib therapy. Monitor for an increase in caffeine-related adverse reactions if coadministration with capmatinib is necessary. Caffeine is a sensitive CYP1A2 substrate and capmatinib is a weak CYP1A2 inhibitor. Coadministration with capmatinib increased caffeine exposure by 134%.
    Afatinib: (Moderate) If the concomitant use of capmatinib and afatinib is necessary, monitor for afatinib-related adverse reactions. If the original dose of afatinib is not tolerated, consider reducing the daily dose of afatinib by 10 mg; resume the previous dose of afatinib as tolerated after discontinuation of capmatinib. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise. Afatinib is a P-glycoprotein (P-gp) substrate and capmatinib is a P-gp inhibitor. Administration with another P-gp inhibitor, given 1 hour before a single dose of afatinib, increased afatinib exposure by 48%; there was no change in afatinib exposure when the P-gp inhibitor was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with the same P-gp inhibitor, and 111% and 105% when the inhibitor was administered 6 hours after afatinib.
    Alogliptin; Metformin: (Moderate) Monitor for an increased risk of metformin-related adverse reactions including lactic acidosis if coadministration with capmatinib is necessary; consider the benefits and risks of concomitant use. Metformin is a substrate of multidrug and toxin extrusion (MATE) and capmatinib is a MATE1 and MATE2K inhibitor. Coadministration may interfere with the renal elimination of metformin and increase metformin exposure.
    Alpelisib: (Major) Avoid coadministration of alpelisib with capmatinib due to increased exposure to alpelisib and the risk of alpelisib-related toxicity. If concomitant use is unavoidable, closely monitor for alpelisib-related adverse reactions. Alpelisib is a BCRP substrate and capmatinib is a BCRP inhibitor.
    Amlodipine; Atorvastatin: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions including myopathy and rhabdomyolysis if coadministration with capmatinib is necessary. Atorvastatin is a P-glycoprotein (P-gp) substrate and a substrate of the efflux transporter BCRP. Capmatinib is a P-gp and BCRP inhibitor. If coadministration is unavoidable, consider a decrease in the atorvastatin dosage in accordance with the approved atorvastatin prescribing information and clinical goals for the patient.
    Amobarbital: (Major) Avoid coadministration of capmatinib and amobarbital due to the risk of decreased capmatinib exposure, which may reduce its efficacy. Capmatinib is a CYP3A substrate and amobarbital is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer decreased capmatinib exposure by 44%.
    Amoxicillin; Clarithromycin; Omeprazole: (Moderate) Monitor for an increase in capmatinib-related adverse reactions if coadministration with clarithromycin is necessary. Capmatinib is a CYP3A substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased capmatinib exposure by 42%.
    Anagrelide: (Moderate) Monitor patients for bleeding and cardiovascular events and titrate doses accordingly if coadministration of anagrelide with capmatinib is necessary. Anagrelide is a CYP1A2 substrate and capmatinib is a weak CYP1A2 inhibitor. Concomitant use may increase anagrelide exposure.
    Apalutamide: (Major) Avoid coadministration of capmatinib and apalutamide due to the risk of decreased capmatinib exposure, which may reduce its efficacy. Capmatinib is a CYP3A substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased capmatinib exposure by 67%.
    Aspirin, ASA; Butalbital; Caffeine: (Major) Avoid coadministration of capmatinib and butalbital due to the risk of decreased capmatinib exposure, which may reduce its efficacy. Capmatinib is a CYP3A substrate and butalbital is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer decreased capmatinib exposure by 44%. (Moderate) Reduction or limitation of the caffeine dosage in medications or caffeine in beverages and food may be necessary during concurrent capmatinib therapy. Monitor for an increase in caffeine-related adverse reactions if coadministration with capmatinib is necessary. Caffeine is a sensitive CYP1A2 substrate and capmatinib is a weak CYP1A2 inhibitor. Coadministration with capmatinib increased caffeine exposure by 134%.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Major) Avoid coadministration of capmatinib and butalbital due to the risk of decreased capmatinib exposure, which may reduce its efficacy. Capmatinib is a CYP3A substrate and butalbital is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer decreased capmatinib exposure by 44%. (Moderate) Reduction or limitation of the caffeine dosage in medications or caffeine in beverages and food may be necessary during concurrent capmatinib therapy. Monitor for an increase in caffeine-related adverse reactions if coadministration with capmatinib is necessary. Caffeine is a sensitive CYP1A2 substrate and capmatinib is a weak CYP1A2 inhibitor. Coadministration with capmatinib increased caffeine exposure by 134%.
    Aspirin, ASA; Caffeine: (Moderate) Reduction or limitation of the caffeine dosage in medications or caffeine in beverages and food may be necessary during concurrent capmatinib therapy. Monitor for an increase in caffeine-related adverse reactions if coadministration with capmatinib is necessary. Caffeine is a sensitive CYP1A2 substrate and capmatinib is a weak CYP1A2 inhibitor. Coadministration with capmatinib increased caffeine exposure by 134%.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Moderate) Reduction or limitation of the caffeine dosage in medications or caffeine in beverages and food may be necessary during concurrent capmatinib therapy. Monitor for an increase in caffeine-related adverse reactions if coadministration with capmatinib is necessary. Caffeine is a sensitive CYP1A2 substrate and capmatinib is a weak CYP1A2 inhibitor. Coadministration with capmatinib increased caffeine exposure by 134%.
    Aspirin, ASA; Caffeine; Orphenadrine: (Moderate) Reduction or limitation of the caffeine dosage in medications or caffeine in beverages and food may be necessary during concurrent capmatinib therapy. Monitor for an increase in caffeine-related adverse reactions if coadministration with capmatinib is necessary. Caffeine is a sensitive CYP1A2 substrate and capmatinib is a weak CYP1A2 inhibitor. Coadministration with capmatinib increased caffeine exposure by 134%.
    Atazanavir: (Moderate) Monitor for an increase in capmatinib-related adverse reactions if coadministration with atazanavir is necessary. Capmatinib is a CYP3A substrate and atazanavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased capmatinib exposure by 42%.
    Atazanavir; Cobicistat: (Moderate) Monitor for an increase in capmatinib-related adverse reactions if coadministration with atazanavir is necessary. Capmatinib is a CYP3A substrate and atazanavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased capmatinib exposure by 42%. (Moderate) Monitor for an increase in capmatinib-related adverse reactions if coadministration with cobicistat is necessary. Capmatinib is a CYP3A substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased capmatinib exposure by 42%.
    Atorvastatin: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions including myopathy and rhabdomyolysis if coadministration with capmatinib is necessary. Atorvastatin is a P-glycoprotein (P-gp) substrate and a substrate of the efflux transporter BCRP. Capmatinib is a P-gp and BCRP inhibitor. If coadministration is unavoidable, consider a decrease in the atorvastatin dosage in accordance with the approved atorvastatin prescribing information and clinical goals for the patient.
    Atorvastatin; Ezetimibe: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions including myopathy and rhabdomyolysis if coadministration with capmatinib is necessary. Atorvastatin is a P-glycoprotein (P-gp) substrate and a substrate of the efflux transporter BCRP. Capmatinib is a P-gp and BCRP inhibitor. If coadministration is unavoidable, consider a decrease in the atorvastatin dosage in accordance with the approved atorvastatin prescribing information and clinical goals for the patient.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Avoid coadministration of capmatinib and phenobarbital due to the risk of decreased capmatinib exposure, which may reduce its efficacy. Capmatinib is a CYP3A substrate and phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased capmatinib exposure by 67%.
    Bendamustine: (Major) Consider the use of an alternative therapy if capmatinib treatment is needed in patients receiving bendamustine. Capmatinib may increase bendamustine exposure, which may increase the risk of adverse reactions (e.g., myelosuppression, infection, hepatotoxicity). Bendamustine is a CYP1A2 substrate and capmatinib is a CYP1A2 inhibitor.
    Berotralstat: (Major) Reduce the berotralstat dose to 110 mg PO once daily in patients chronically taking capmatinib. Concurrent use may increase berotralstat exposure and the risk of adverse effects. Berotralstat is a P-gp and BCRP substrate and capmatinib is a P-gp and BCRP inhibitor. Coadministration with another P-gp and BCRP inhibitor increased berotralstat exposure by 69%.
    Betrixaban: (Major) Avoid betrixaban use in patients with severe renal impairment receiving capmatinib. Reduce betrixaban dosage to 80 mg PO once followed by 40 mg PO once daily in all other patients receiving capmatinib. Concurrent use may increase betrixaban exposure resulting in an increased bleeding risk; monitor patients closely for signs and symptoms of bleeding. Betrixaban is a P-gp substrate; capmatinib is a P-gp inhibitor. Coadministration of other P-gp inhibitors increased betrixaban exposure by 2 to 3 fold.
    Bexarotene: (Major) Avoid coadministration of capmatinib and bexarotene due to the risk of decreased capmatinib exposure, which may reduce its efficacy. Capmatinib is a CYP3A substrate and bexarotene is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer decreased capmatinib exposure by 44%.
    Bictegravir; Emtricitabine; Tenofovir Alafenamide: (Moderate) Coadministration of tenofovir alafenamide with capmatinib may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-glycoprotein (P-gp) and BCRP substrate and capmatinib is a P-gp and BCRP inhibitor.
    Bosentan: (Major) Avoid coadministration of capmatinib and bosentan due to the risk of decreased capmatinib exposure, which may reduce its efficacy. Capmatinib is a CYP3A substrate and bosentan is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer decreased capmatinib exposure by 44%.
    Bupivacaine; Lidocaine: (Moderate) Monitor for an increase in lidocaine-related adverse reactions if coadministration with capmatinib is necessary. Monitor lidocaine concentrations if clinically indicated and lidocaine is being given intravenously. Lidocaine is a CYP1A2 substrate and capmatinib is a weak CYP1A2 inhibitor. Concomitant use may increase lidocaine exposure.
    Butabarbital: (Major) Avoid coadministration of capmatinib and butabarbital due to the risk of decreased capmatinib exposure, which may reduce its efficacy. Capmatinib is a CYP3A substrate and butabarbital is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer decreased capmatinib exposure by 44%.
    Butalbital; Acetaminophen: (Major) Avoid coadministration of capmatinib and butalbital due to the risk of decreased capmatinib exposure, which may reduce its efficacy. Capmatinib is a CYP3A substrate and butalbital is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer decreased capmatinib exposure by 44%.
    Butalbital; Acetaminophen; Caffeine: (Major) Avoid coadministration of capmatinib and butalbital due to the risk of decreased capmatinib exposure, which may reduce its efficacy. Capmatinib is a CYP3A substrate and butalbital is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer decreased capmatinib exposure by 44%. (Moderate) Reduction or limitation of the caffeine dosage in medications or caffeine in beverages and food may be necessary during concurrent capmatinib therapy. Monitor for an increase in caffeine-related adverse reactions if coadministration with capmatinib is necessary. Caffeine is a sensitive CYP1A2 substrate and capmatinib is a weak CYP1A2 inhibitor. Coadministration with capmatinib increased caffeine exposure by 134%.
    Butalbital; Acetaminophen; Caffeine; Codeine: (Major) Avoid coadministration of capmatinib and butalbital due to the risk of decreased capmatinib exposure, which may reduce its efficacy. Capmatinib is a CYP3A substrate and butalbital is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer decreased capmatinib exposure by 44%. (Moderate) Reduction or limitation of the caffeine dosage in medications or caffeine in beverages and food may be necessary during concurrent capmatinib therapy. Monitor for an increase in caffeine-related adverse reactions if coadministration with capmatinib is necessary. Caffeine is a sensitive CYP1A2 substrate and capmatinib is a weak CYP1A2 inhibitor. Coadministration with capmatinib increased caffeine exposure by 134%.
    Caffeine: (Moderate) Reduction or limitation of the caffeine dosage in medications or caffeine in beverages and food may be necessary during concurrent capmatinib therapy. Monitor for an increase in caffeine-related adverse reactions if coadministration with capmatinib is necessary. Caffeine is a sensitive CYP1A2 substrate and capmatinib is a weak CYP1A2 inhibitor. Coadministration with capmatinib increased caffeine exposure by 134%.
    Caffeine; Sodium Benzoate: (Moderate) Reduction or limitation of the caffeine dosage in medications or caffeine in beverages and food may be necessary during concurrent capmatinib therapy. Monitor for an increase in caffeine-related adverse reactions if coadministration with capmatinib is necessary. Caffeine is a sensitive CYP1A2 substrate and capmatinib is a weak CYP1A2 inhibitor. Coadministration with capmatinib increased caffeine exposure by 134%.
    Canagliflozin; Metformin: (Moderate) Monitor for an increased risk of metformin-related adverse reactions including lactic acidosis if coadministration with capmatinib is necessary; consider the benefits and risks of concomitant use. Metformin is a substrate of multidrug and toxin extrusion (MATE) and capmatinib is a MATE1 and MATE2K inhibitor. Coadministration may interfere with the renal elimination of metformin and increase metformin exposure.
    Carbamazepine: (Major) Avoid coadministration of capmatinib and carbamazepine due to the risk of decreased capmatinib exposure, which may reduce its efficacy. Capmatinib is a CYP3A substrate and carbamazepine is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased capmatinib exposure by 67%.
    Cenobamate: (Major) Avoid coadministration of capmatinib and cenobamate due to the risk of decreased capmatinib exposure, which may reduce its efficacy. Capmatinib is a CYP3A substrate and cenobamate is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer decreased capmatinib exposure by 44%.
    Ceritinib: (Moderate) Monitor for an increase in capmatinib-related adverse reactions if coadministration with ceritinib is necessary. Capmatinib is a CYP3A substrate and ceritinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased capmatinib exposure by 42%.
    Chloramphenicol: (Moderate) Monitor for an increase in capmatinib-related adverse reactions if coadministration with chloramphenicol is necessary. Capmatinib is a CYP3A substrate and chloramphenicol is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased capmatinib exposure by 42%.
    Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
    Clarithromycin: (Moderate) Monitor for an increase in capmatinib-related adverse reactions if coadministration with clarithromycin is necessary. Capmatinib is a CYP3A substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased capmatinib exposure by 42%.
    Clozapine: (Moderate) Consider a clozapine dose reduction if coadministered with capmatinib and monitor for adverse reactions. A clinically relevant increase in the plasma concentration of clozapine may occur during concurrent use. Clozapine is a CYP1A2 substrate. Capmatinib is a weak CYP1A2 inhibitor.
    Cobicistat: (Moderate) Monitor for an increase in capmatinib-related adverse reactions if coadministration with cobicistat is necessary. Capmatinib is a CYP3A substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased capmatinib exposure by 42%.
    Colchicine: (Major) Due to the risk for serious colchicine toxicity including multi-organ failure and death, avoid coadministration of colchicine and capmatinib in patients with normal renal and hepatic function unless the use of both agents is imperative. Coadministration is contraindicated in patients with renal or hepatic impairment because colchicine accumulation may be greater in these populations. Capmatinib can inhibit colchicine's metabolism via P-glycoprotein (P-gp), resulting in increased colchicine exposure. If coadministration in patients with normal renal and hepatic function cannot be avoided, adjust the dose of colchicine by either reducing the daily dose or the dosage frequency, and carefully monitor for colchicine toxicity. Specific dosage adjustment recommendations are available for the Colcrys product for patients who have taken capmatinib in the past 14 days or require concurrent use: for prophylaxis of gout flares, if the original dose is 0.6 mg twice daily, decrease to 0.3 mg once daily or if the original dose is 0.6 mg once daily, decrease to 0.3 mg once every other day; for treatment of gout flares, give 0.6 mg as a single dose, then 0.3 mg 1 hour later, and do not repeat for at least 3 days; for familial Mediterranean fever, do not exceed a 0.6 mg/day.
    Cyclosporine: (Moderate) Closely monitor cyclosporine whole blood trough concentrations as appropriate and watch for cyclosporine-related adverse reactions if coadministration with capmatinib is necessary. The dose of cyclosporine may need to be adjusted. Concurrent use may increase cyclosporine exposure causing an increased risk for cyclosporine-related adverse events. Cyclosporine is a P-glycoprotein (P-gp) substrate and capmatinib is a P-gp inhibitor.
    Dabigatran: (Moderate) Monitor for an increase in dabigatran-related adverse reactions if coadministration with capmatinib is necessary in patients with CrCL greater than 50 mL/minute. Avoid coadministration in patients with CrCL less than 50 mL/minute when dabigatran is administered for treatment or reduction in risk of recurrence of deep venous thrombosis (DVT) or pulmonary embolism (PE) or prophylaxis of DVT or PE following hip replacement surgery. Avoid coadministration in patients with CrCL less than 30 mL/minute in patients with non-valvular atrial fibrillation. Serum concentrations of dabigatran are expected to be higher in patients with renal impairment compared to patients with normal renal function. Dabigatran is a P-glycoprotein substrate and capmatinib is a P-gp inhibitor.
    Dabrafenib: (Major) Avoid coadministration of capmatinib and dabrafenib due to the risk of decreased capmatinib exposure, which may reduce its efficacy. Capmatinib is a CYP3A substrate and dabrafenib is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer decreased capmatinib exposure by 44%.
    Dapagliflozin; Metformin: (Moderate) Monitor for an increased risk of metformin-related adverse reactions including lactic acidosis if coadministration with capmatinib is necessary; consider the benefits and risks of concomitant use. Metformin is a substrate of multidrug and toxin extrusion (MATE) and capmatinib is a MATE1 and MATE2K inhibitor. Coadministration may interfere with the renal elimination of metformin and increase metformin exposure.
    Darunavir: (Moderate) Monitor for an increase in capmatinib-related adverse reactions if coadministration with darunavir is necessary. Capmatinib is a CYP3A substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased capmatinib exposure by 42%.
    Darunavir; Cobicistat: (Moderate) Monitor for an increase in capmatinib-related adverse reactions if coadministration with cobicistat is necessary. Capmatinib is a CYP3A substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased capmatinib exposure by 42%. (Moderate) Monitor for an increase in capmatinib-related adverse reactions if coadministration with darunavir is necessary. Capmatinib is a CYP3A substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased capmatinib exposure by 42%.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) Coadministration of tenofovir alafenamide with capmatinib may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-glycoprotein (P-gp) and BCRP substrate and capmatinib is a P-gp and BCRP inhibitor. (Moderate) Monitor for an increase in capmatinib-related adverse reactions if coadministration with cobicistat is necessary. Capmatinib is a CYP3A substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased capmatinib exposure by 42%. (Moderate) Monitor for an increase in capmatinib-related adverse reactions if coadministration with darunavir is necessary. Capmatinib is a CYP3A substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased capmatinib exposure by 42%.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Monitor for an increase in capmatinib-related adverse reactions if coadministration with ritonavir is necessary. Capmatinib is a CYP3A substrate and ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased capmatinib exposure by 42%. (Moderate) Monitor for an increase in dasabuvir-related adverse reactions if coadministration with capmatinib is necessary. Dasabuvir is a substrate of BCRP and P-glycoprotein (P-gp). Capmatinib is a BCRP and P-gp inhibitor. Concomitant use may increase dasabuvir plasma concentrations. (Moderate) Monitor for an increase in ombitasvir-related adverse reactions if coadministration with capmatinib is necessary. Ombitasvir is a P-glycoprotein (P-gp) and BCRP substrate. Capmatinib is a P-gp and BCRP inhibitor. (Moderate) Monitor for an increase in paritaprevir-related adverse reactions if coadministration with capmatinib is necessary. Paritaprevir is a P-glycoprotein (P-gp) and BCRP substrate. Capmatinib is a P-gp and BCRP inhibitor. Concomitant use may increase paritaprevir exposure.
    Delavirdine: (Moderate) Monitor for an increase in capmatinib-related adverse reactions if coadministration with delavirdine is necessary. Capmatinib is a CYP3A substrate and delavirdine is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased capmatinib exposure by 42%.
    Dexamethasone: (Major) Avoid coadministration of capmatinib and dexamethasone due to the risk of decreased capmatinib exposure, which may reduce its efficacy. Capmatinib is a CYP3A substrate and dexamethasone is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer decreased capmatinib exposure by 44%.
    Digoxin: (Moderate) Monitor for an increase in digoxin-related adverse reactions if coadministration with capmatinib is necessary. Measure serum digoxin concentrations before initiating concomitant drugs; adjust the digoxin dosage or dose frequency as indicated, and continue to monitor digoxin concentrations and clinical response to guide therapy. Digoxin is a P-glycoprotein (P-gp) substrate and capmatinib is a P-gp inhibitor. Coadministration with capmatinib increased digoxin exposure by 47%.
    Dolutegravir: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with capmatinib. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a P-glycoprotein (P-gp) substrate and capmatinib is a P-gp inhibitor.
    Dolutegravir; Lamivudine: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with capmatinib. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a P-glycoprotein (P-gp) substrate and capmatinib is a P-gp inhibitor.
    Dolutegravir; Rilpivirine: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with capmatinib. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a P-glycoprotein (P-gp) substrate and capmatinib is a P-gp inhibitor.
    Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with capmatinib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-glycoprotein (P-gp) and BCRP substrate and capmatinib is a P-gp and BCRP inhibitor.
    Doxorubicin Liposomal: (Major) Avoid coadministration of capmatinib with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Capmatinib is a P-gp inhibitor and doxorubicin is a P-gp substrate. Concurrent use of P-gp inhibitors with doxorubicin has resulted in clinically significant interactions.
    Doxorubicin: (Major) Avoid coadministration of capmatinib with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Capmatinib is a P-gp inhibitor and doxorubicin is a P-gp substrate. Concurrent use of P-gp inhibitors with doxorubicin has resulted in clinically significant interactions.
    Edoxaban: (Major) If coadministered with capmatinib, a P-gp inhibitor, dosage reduction of edoxaban, a P-gp substrate, may be necessary for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism (PE). An edoxaban dose reduction to 30 mg PO once daily is recommended by the manufacturer for use with certain P-gp inhibitors; however, because use of concomitant P-gp inhibitors was limited to only certain drugs that inhibit P-gp in DVT/PE clinical trials, clinicians should use professional judgment and guide edoxaban dose adjustments based on patient response if coadministered with capmatinib. Based on clinical experience in patients with non-valvular atrial fibrillation no dose reduction is recommended for concomitant use of capmatinib. Increased concentrations of edoxaban may occur during concomitant use of capmatinib; monitor for increased adverse effects of edoxaban.
    Efavirenz: (Major) Avoid coadministration of efavirenz and rifampin due to the risk of decreased capmatinib exposure, which may reduce its efficacy. Capmatinib is a CYP3A substrate and efavirenz is a strong CYP3A4 inducer. Coadministration with efavirenz decreased capmatinib exposure by 44%.
    Efavirenz; Emtricitabine; Tenofovir: (Major) Avoid coadministration of efavirenz and rifampin due to the risk of decreased capmatinib exposure, which may reduce its efficacy. Capmatinib is a CYP3A substrate and efavirenz is a strong CYP3A4 inducer. Coadministration with efavirenz decreased capmatinib exposure by 44%. (Moderate) Coadministration of tenofovir disoproxil fumarate with capmatinib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-glycoprotein (P-gp) and BCRP substrate and capmatinib is a P-gp and BCRP inhibitor.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Avoid coadministration of efavirenz and rifampin due to the risk of decreased capmatinib exposure, which may reduce its efficacy. Capmatinib is a CYP3A substrate and efavirenz is a strong CYP3A4 inducer. Coadministration with efavirenz decreased capmatinib exposure by 44%. (Moderate) Coadministration of tenofovir disoproxil fumarate with capmatinib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-glycoprotein (P-gp) and BCRP substrate and capmatinib is a P-gp and BCRP inhibitor.
    Elagolix: (Major) Avoid coadministration of capmatinib and elagolix due to the risk of decreased capmatinib exposure, which may reduce its efficacy. Capmatinib is a CYP3A substrate and elagolix is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer decreased capmatinib exposure by 44%.
    Elagolix; Estradiol; Norethindrone acetate: (Major) Avoid coadministration of capmatinib and elagolix due to the risk of decreased capmatinib exposure, which may reduce its efficacy. Capmatinib is a CYP3A substrate and elagolix is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer decreased capmatinib exposure by 44%.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Moderate) Coadministration of tenofovir alafenamide with capmatinib may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-glycoprotein (P-gp) and BCRP substrate and capmatinib is a P-gp and BCRP inhibitor. (Moderate) Monitor for an increase in capmatinib-related adverse reactions if coadministration with cobicistat is necessary. Capmatinib is a CYP3A substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased capmatinib exposure by 42%.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with capmatinib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-glycoprotein (P-gp) and BCRP substrate and capmatinib is a P-gp and BCRP inhibitor. (Moderate) Monitor for an increase in capmatinib-related adverse reactions if coadministration with cobicistat is necessary. Capmatinib is a CYP3A substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased capmatinib exposure by 42%.
    Empagliflozin; Linagliptin; Metformin: (Moderate) Monitor for an increased risk of metformin-related adverse reactions including lactic acidosis if coadministration with capmatinib is necessary; consider the benefits and risks of concomitant use. Metformin is a substrate of multidrug and toxin extrusion (MATE) and capmatinib is a MATE1 and MATE2K inhibitor. Coadministration may interfere with the renal elimination of metformin and increase metformin exposure.
    Empagliflozin; Metformin: (Moderate) Monitor for an increased risk of metformin-related adverse reactions including lactic acidosis if coadministration with capmatinib is necessary; consider the benefits and risks of concomitant use. Metformin is a substrate of multidrug and toxin extrusion (MATE) and capmatinib is a MATE1 and MATE2K inhibitor. Coadministration may interfere with the renal elimination of metformin and increase metformin exposure.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Moderate) Coadministration of tenofovir alafenamide with capmatinib may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-glycoprotein (P-gp) and BCRP substrate and capmatinib is a P-gp and BCRP inhibitor.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with capmatinib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-glycoprotein (P-gp) and BCRP substrate and capmatinib is a P-gp and BCRP inhibitor.
    Emtricitabine; Tenofovir alafenamide: (Moderate) Coadministration of tenofovir alafenamide with capmatinib may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-glycoprotein (P-gp) and BCRP substrate and capmatinib is a P-gp and BCRP inhibitor.
    Emtricitabine; Tenofovir disoproxil fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with capmatinib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-glycoprotein (P-gp) and BCRP substrate and capmatinib is a P-gp and BCRP inhibitor.
    Enzalutamide: (Major) Avoid coadministration of capmatinib and enzalutamide due to the risk of decreased capmatinib exposure which may reduce its efficacy. Capmatinib is a CYP3A substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased capmatinib exposure by 67%.
    Ergotamine; Caffeine: (Moderate) Reduction or limitation of the caffeine dosage in medications or caffeine in beverages and food may be necessary during concurrent capmatinib therapy. Monitor for an increase in caffeine-related adverse reactions if coadministration with capmatinib is necessary. Caffeine is a sensitive CYP1A2 substrate and capmatinib is a weak CYP1A2 inhibitor. Coadministration with capmatinib increased caffeine exposure by 134%.
    Ertugliflozin; Metformin: (Moderate) Monitor for an increased risk of metformin-related adverse reactions including lactic acidosis if coadministration with capmatinib is necessary; consider the benefits and risks of concomitant use. Metformin is a substrate of multidrug and toxin extrusion (MATE) and capmatinib is a MATE1 and MATE2K inhibitor. Coadministration may interfere with the renal elimination of metformin and increase metformin exposure.
    Eslicarbazepine: (Major) Avoid coadministration of capmatinib and eslicarbazepine due to the risk of decreased capmatinib exposure, which may reduce its efficacy. Capmatinib is a CYP3A substrate and eslicarbazepine is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer decreased capmatinib exposure by 44%.
    Etravirine: (Major) Avoid coadministration of capmatinib and etravirine due to the risk of decreased capmatinib exposure, which may reduce its efficacy. Capmatinib is a CYP3A substrate and etravirine is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer decreased capmatinib exposure by 44%.
    Everolimus: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions if coadministration with capmatinib is necessary. The dose of everolimus may need to be reduced. Everolimus is a P-glycoprotein (P-gp) substrate and capmatinib is a P-gp inhibitor. Coadministration with P-gp inhibitors may decrease the efflux of everolimus from intestinal cells and increase everolimus blood concentrations.
    Fosamprenavir: (Moderate) Monitor for an increase in treatment-related adverse reactions if coadministration of capmatinib with fosamprenavir is necessary. Capmatinib is a CYP3A substrate and a P-glycoprotein (P-gp) inhibitor. Fosamprenavir is a strong CYP3A4 inhibitor and a P-gp substrate. Coadministration with another strong CYP3A4 inhibitor increased capmatinib exposure by 42%. Inhibitors of P-gp may increase fosamprenavir exposure.
    Fosphenytoin: (Major) Avoid coadministration of capmatinib and fosphenytoin due to the risk of decreased capmatinib exposure, which may reduce its efficacy. Capmatinib is a CYP3A substrate and fosphenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased capmatinib exposure by 67%.
    Glecaprevir; Pibrentasvir: (Moderate) Caution is advised with coadministration of glecaprevir and capmatinib as increased plasma concentrations of glecaprevir may occur resulting in increased risk of glecaprevir-related adverse events. Glecaprevir is a substrate of P-glycoprotein (P-gp) and BCRP and capmatinib is a P-gp and BCRP inhibitor. (Moderate) Caution is advised with coadministration of pibrentasvir and capmatinib as increased plasma concentrations of pibrentasvir may occur resulting in increased risk of pibrentasvir-related adverse events. Pibrentasvir is a substrate of P-glycoprotein (P-gp) and BCRP. Capmatinib is a P-gp and BCRP inhibitor.
    Glipizide; Metformin: (Moderate) Monitor for an increased risk of metformin-related adverse reactions including lactic acidosis if coadministration with capmatinib is necessary; consider the benefits and risks of concomitant use. Metformin is a substrate of multidrug and toxin extrusion (MATE) and capmatinib is a MATE1 and MATE2K inhibitor. Coadministration may interfere with the renal elimination of metformin and increase metformin exposure.
    Glyburide: (Moderate) Monitor blood sugars and watch for an increase in glyburide-related adverse reactions, such as hypoglycemia, if coadministration with capmatinib is necessary. Glyburide is a substrate of P-glycoprotein (P-gp) and BCRP. Capmatinib inhibits both P-gp and BCRP. Concomitant use may increase glyburide exposure.
    Glyburide; Metformin: (Moderate) Monitor blood sugars and watch for an increase in glyburide-related adverse reactions, such as hypoglycemia, if coadministration with capmatinib is necessary. Glyburide is a substrate of P-glycoprotein (P-gp) and BCRP. Capmatinib inhibits both P-gp and BCRP. Concomitant use may increase glyburide exposure. (Moderate) Monitor for an increased risk of metformin-related adverse reactions including lactic acidosis if coadministration with capmatinib is necessary; consider the benefits and risks of concomitant use. Metformin is a substrate of multidrug and toxin extrusion (MATE) and capmatinib is a MATE1 and MATE2K inhibitor. Coadministration may interfere with the renal elimination of metformin and increase metformin exposure.
    Grapefruit juice: (Major) Advise patients to avoid grapefruit and grapefruit juice due to increased capatinib exposure resulting in treatment-related adverse events. Capatinib is a CYP3A4 substrate; grapefruit is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased capmatinib exposure by 42%.
    Idelalisib: (Moderate) Monitor for an increase in capmatinib-related adverse reactions if coadministration with idelalisib is necessary. Capmatinib is a CYP3A substrate and idelalisib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased capmatinib exposure by 42%.
    Indinavir: (Moderate) Monitor for an increase in treatment-related adverse reactions if coadministration of capmatinib with indinavir is necessary. Capmatinib is a CYP3A substrate and a P-glycoprotein inhibitor. Indinavir is a strong CYP3A4 inhibitor and a P-gp substrate. Coadministration with another strong CYP3A4 inhibitor increased capmatinib exposure by 42%. Coadministration with P-gp inhibitors may increase indinavir exposure.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid coadministration of capmatinib and rifampin due to the risk of decreased capmatinib exposure, which may reduce its efficacy. Capmatinib is a CYP3A substrate and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin decreased capmatinib exposure by 67%.
    Isoniazid, INH; Rifampin: (Major) Avoid coadministration of capmatinib and rifampin due to the risk of decreased capmatinib exposure, which may reduce its efficacy. Capmatinib is a CYP3A substrate and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin decreased capmatinib exposure by 67%.
    Itraconazole: (Moderate) Monitor for an increase in capmatinib-related adverse reactions if coadministration with itraconazole is necessary. Capmatinib is a CYP3A substrate and itraconazole is a strong CYP3A4 inhibitor. Coadministration with itraconazole increased capmatinib exposure by 42%.
    Ketoconazole: (Moderate) Monitor for an increase in capmatinib-related adverse reactions if coadministration with ketoconazole is necessary. Capmatinib is a CYP3A substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased capmatinib exposure by 42%.
    Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with capmatinib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-glycoprotein (P-gp) and BCRP substrate and capmatinib is a P-gp and BCRP inhibitor.
    Lansoprazole; Amoxicillin; Clarithromycin: (Moderate) Monitor for an increase in capmatinib-related adverse reactions if coadministration with clarithromycin is necessary. Capmatinib is a CYP3A substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased capmatinib exposure by 42%.
    Lapatinib: (Moderate) Monitor for an increase in lapatinib-related adverse reactions if coadministration with capmatinib is necessary. Lapatinib is a P-glycoprotein (P-gp) substrate and capmatinib is a P-gp inhibitor. Increased plasma concentrations of lapatinib are likely.
    Lefamulin: (Major) Avoid coadministration of capmatinib with oral lefamulin unless the benefits outweigh the risks as concurrent use may increase lefamulin exposure and adverse effects; capmatinib may be administered with intravenous lefamulin. Lefamulin is a P-gp substrate and capmatinib is a P-gp inhibitor.
    Levoketoconazole: (Moderate) Monitor for an increase in capmatinib-related adverse reactions if coadministration with ketoconazole is necessary. Capmatinib is a CYP3A substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased capmatinib exposure by 42%.
    Lidocaine: (Moderate) Monitor for an increase in lidocaine-related adverse reactions if coadministration with capmatinib is necessary. Monitor lidocaine concentrations if clinically indicated and lidocaine is being given intravenously. Lidocaine is a CYP1A2 substrate and capmatinib is a weak CYP1A2 inhibitor. Concomitant use may increase lidocaine exposure.
    Lidocaine; Epinephrine: (Moderate) Monitor for an increase in lidocaine-related adverse reactions if coadministration with capmatinib is necessary. Monitor lidocaine concentrations if clinically indicated and lidocaine is being given intravenously. Lidocaine is a CYP1A2 substrate and capmatinib is a weak CYP1A2 inhibitor. Concomitant use may increase lidocaine exposure.
    Lidocaine; Prilocaine: (Moderate) Monitor for an increase in lidocaine-related adverse reactions if coadministration with capmatinib is necessary. Monitor lidocaine concentrations if clinically indicated and lidocaine is being given intravenously. Lidocaine is a CYP1A2 substrate and capmatinib is a weak CYP1A2 inhibitor. Concomitant use may increase lidocaine exposure.
    Linagliptin; Metformin: (Moderate) Monitor for an increased risk of metformin-related adverse reactions including lactic acidosis if coadministration with capmatinib is necessary; consider the benefits and risks of concomitant use. Metformin is a substrate of multidrug and toxin extrusion (MATE) and capmatinib is a MATE1 and MATE2K inhibitor. Coadministration may interfere with the renal elimination of metformin and increase metformin exposure.
    Lonafarnib: (Moderate) Monitor for an increase in capmatinib-related adverse reactions if coadministration with lonafarnib is necessary. Capmatinib is a CYP3A substrate and lonafarnib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased capmatinib exposure by 42%.
    Loperamide: (Moderate) Monitor for an increase in loperamide-related adverse reactions, including CNS effects (e.g., drowsiness, dizziness) and cardiac effects (e.g., QT prolongation) if coadministration with capmatinib is necessary. Loperamide is a P-glycoprotein (P-gp) substrate and capmatinib is a P-gp inhibitor. Coadministration with other P-gp inhibitors has increased loperamide exposure by 2-fold to 3-fold.
    Loperamide; Simethicone: (Moderate) Monitor for an increase in loperamide-related adverse reactions, including CNS effects (e.g., drowsiness, dizziness) and cardiac effects (e.g., QT prolongation) if coadministration with capmatinib is necessary. Loperamide is a P-glycoprotein (P-gp) substrate and capmatinib is a P-gp inhibitor. Coadministration with other P-gp inhibitors has increased loperamide exposure by 2-fold to 3-fold.
    Lopinavir; Ritonavir: (Moderate) Monitor for an increase in capmatinib-related adverse reactions if coadministration with ritonavir is necessary. Capmatinib is a CYP3A substrate and ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased capmatinib exposure by 42%.
    Lorlatinib: (Major) Avoid coadministration of capmatinib and lorlatinib due to the risk of decreased capmatinib exposure, which may reduce its efficacy. Capmatinib is a CYP3A substrate and lorlatinib is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer decreased capmatinib exposure by 44%.
    Lumacaftor; Ivacaftor: (Major) Avoid coadministration of capmatinib and lumacaftor; ivacaftor due to the risk of decreased capmatinib exposure, which may reduce its efficacy. Capmatinib is a CYP3A substrate and lumacaftor is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased capmatinib exposure by 67%.
    Lumacaftor; Ivacaftor: (Major) Avoid coadministration of capmatinib and lumacaftor; ivacaftor due to the risk of decreased capmatinib exposure, which may reduce its efficacy. Capmatinib is a CYP3A substrate and lumacaftor is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased capmatinib exposure by 67%.
    Maraviroc: (Moderate) Monitor for an increase in maraviroc-related adverse reactions if coadministration with capmatinib is necessary. Maraviroc is a P-glycoprotein (P-gp) substrate and capmatinib is a P-gp inhibitor. Concomitant use may increase maraviroc exposure.
    Mefloquine: (Moderate) Monitor for an increase in mefloquine-related adverse reactions if coadministration with capmatinib is necessary. Mefloquine is a P-glycoprotein (P-gp) substrate and capmatinib is a P-gp inhibitor.
    Melatonin: (Moderate) Monitor for an increase in melatonin-related adverse reactions if coadministration with capmatinib is necessary. Melatonin is a sensitive CYP1A2 substrate and capmatinib is a weak CYP1A2 inhibitor.
    Mephobarbital: (Major) Avoid coadministration of capmatinib and mephobarbital due to the risk of decreased capmatinib exposure, which may reduce its efficacy. Capmatinib is a CYP3A substrate and mephobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased capmatinib exposure by 67%.
    Metformin: (Moderate) Monitor for an increased risk of metformin-related adverse reactions including lactic acidosis if coadministration with capmatinib is necessary; consider the benefits and risks of concomitant use. Metformin is a substrate of multidrug and toxin extrusion (MATE) and capmatinib is a MATE1 and MATE2K inhibitor. Coadministration may interfere with the renal elimination of metformin and increase metformin exposure.
    Metformin; Repaglinide: (Moderate) Monitor for an increased risk of metformin-related adverse reactions including lactic acidosis if coadministration with capmatinib is necessary; consider the benefits and risks of concomitant use. Metformin is a substrate of multidrug and toxin extrusion (MATE) and capmatinib is a MATE1 and MATE2K inhibitor. Coadministration may interfere with the renal elimination of metformin and increase metformin exposure.
    Metformin; Rosiglitazone: (Moderate) Monitor for an increased risk of metformin-related adverse reactions including lactic acidosis if coadministration with capmatinib is necessary; consider the benefits and risks of concomitant use. Metformin is a substrate of multidrug and toxin extrusion (MATE) and capmatinib is a MATE1 and MATE2K inhibitor. Coadministration may interfere with the renal elimination of metformin and increase metformin exposure.
    Metformin; Saxagliptin: (Moderate) Monitor for an increased risk of metformin-related adverse reactions including lactic acidosis if coadministration with capmatinib is necessary; consider the benefits and risks of concomitant use. Metformin is a substrate of multidrug and toxin extrusion (MATE) and capmatinib is a MATE1 and MATE2K inhibitor. Coadministration may interfere with the renal elimination of metformin and increase metformin exposure.
    Metformin; Sitagliptin: (Moderate) Monitor for an increased risk of metformin-related adverse reactions including lactic acidosis if coadministration with capmatinib is necessary; consider the benefits and risks of concomitant use. Metformin is a substrate of multidrug and toxin extrusion (MATE) and capmatinib is a MATE1 and MATE2K inhibitor. Coadministration may interfere with the renal elimination of metformin and increase metformin exposure.
    Methohexital: (Major) Avoid coadministration of capmatinib and methohexital due to the risk of decreased capmatinib exposure, which may reduce its efficacy. Capmatinib is a CYP3A substrate and methohexital is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer decreased capmatinib exposure by 44%.
    Mexiletine: (Moderate) Monitor for an increase in mexiletine-related adverse reactions if coadministration with capmatinib is necessary. Monitor mexiletine drug concentrations as clinically indicated. Mexiletine is a CYP1A2 substrate and capmatinib is a weak CYP1A2 inhibitor. Concomitant use may increase mexiletine exposure.
    Mifepristone: (Moderate) Monitor for an increase in capmatinib-related adverse reactions if coadministration with mifepristone is necessary. Capmatinib is a CYP3A substrate and mifepristone is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased capmatinib exposure by 42%. The interaction is most likely when mifepristone is used chronically to treat hormonal conditions, such as Cushing's disease. The clinical significance of this interaction with the short-term use of mifepristone for termination of pregnancy is unknown.
    Mitotane: (Major) Avoid coadministration of capmatinib and mitotane due to the risk of decreased capmatinib exposure, which may reduce its efficacy. Capmatinib is a CYP3A substrate and mitotane is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased capmatinib exposure by 67%.
    Modafinil: (Major) Avoid coadministration of capmatinib and modafinil due to the risk of decreased capmatinib exposure, which may reduce its efficacy. Capmatinib is a CYP3A substrate and modafinil is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer decreased capmatinib exposure by 44%.
    Morphine: (Moderate) Monitor for an increase in morphine-related adverse reactions, including hypotension, sedation, and respiratory depression, if coadministration with capmatinib is necessary; decrease the dose of either drug as necessary. Morphine is a P-glycoprotein (P-gp) substrate and capmatinib is a P-gp inhibitor. Coadministration with P-gp inhibitors can increase morphine exposure by about 2-fold.
    Morphine; Naltrexone: (Moderate) Monitor for an increase in morphine-related adverse reactions, including hypotension, sedation, and respiratory depression, if coadministration with capmatinib is necessary; decrease the dose of either drug as necessary. Morphine is a P-glycoprotein (P-gp) substrate and capmatinib is a P-gp inhibitor. Coadministration with P-gp inhibitors can increase morphine exposure by about 2-fold.
    Nafcillin: (Major) Avoid coadministration of capmatinib and nafcillin due to the risk of decreased capmatinib exposure, which may reduce its efficacy. Capmatinib is a CYP3A substrate and nafcillin is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer decreased capmatinib exposure by 44%.
    Naldemedine: (Moderate) Monitor for potential naldemedine-related adverse reactions if coadministered with capmatinib. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a P-gp substrate; capmatinib is a P-gp inhibitor.
    Nanoparticle Albumin-Bound Sirolimus: (Major) Avoid coadministration of sirolimus with capmatinib as concurrent use may increase sirolimus exposure and risk of toxicity. Alternative agents with lesser interaction potential with sirolimus should be considered. Sirolimus is a P-gp substrate and capmatinib is a P-gp inhibitor.
    Nefazodone: (Moderate) Monitor for an increase in capmatinib-related adverse reactions if coadministration with nefazodone is necessary. Capmatinib is a CYP3A substrate and nefazodone is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased capmatinib exposure by 42%.
    Nelfinavir: (Moderate) Monitor for an increase in capmatinib-related adverse reactions if coadministration with nelfinavir is necessary. Capmatinib is a CYP3A substrate and nelfinavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased capmatinib exposure by 42%.
    Nevirapine: (Major) Avoid coadministration of capmatinib and nevirapine due to the risk of decreased capmatinib exposure, which may reduce its efficacy. Capmatinib is a CYP3A substrate and nevirapine is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer decreased capmatinib exposure by 44%.
    Nirmatrelvir; Ritonavir: (Moderate) Monitor for an increase in capmatinib-related adverse reactions if coadministration with ritonavir is necessary. Capmatinib is a CYP3A substrate and ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased capmatinib exposure by 42%.
    Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Monitor for an increase in capmatinib-related adverse reactions if coadministration with ritonavir is necessary. Capmatinib is a CYP3A substrate and ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased capmatinib exposure by 42%. (Moderate) Monitor for an increase in ombitasvir-related adverse reactions if coadministration with capmatinib is necessary. Ombitasvir is a P-glycoprotein (P-gp) and BCRP substrate. Capmatinib is a P-gp and BCRP inhibitor. (Moderate) Monitor for an increase in paritaprevir-related adverse reactions if coadministration with capmatinib is necessary. Paritaprevir is a P-glycoprotein (P-gp) and BCRP substrate. Capmatinib is a P-gp and BCRP inhibitor. Concomitant use may increase paritaprevir exposure.
    Omeprazole; Amoxicillin; Rifabutin: (Major) Avoid coadministration of capmatinib and rifabutin due to the risk of decreased capmatinib exposure, which may reduce its efficacy. Capmatinib is a CYP3A substrate and rifabutin is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer decreased capmatinib exposure by 44%.
    Pazopanib: (Major) Avoid coadministration of pazopanib and capmatinib due to the potential for increased pazopanib exposure. Pazopanib is a P-glycoprotein (P-gp) and BCRP substrate. Capmatinib is a P-gp and BCRP inhibitor. Consider selection of an alternative concomitant medication with no or minimal potential to inhibit P-gp or BCRP.
    Pentobarbital: (Major) Avoid coadministration of capmatinib and pentobarbital due to the risk of decreased capmatinib exposure, which may reduce its efficacy. Capmatinib is a CYP3A substrate and pentobarbital is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer decreased capmatinib exposure by 44%.
    Pexidartinib: (Major) Avoid coadministration of capmatinib and pexidartinib due to the risk of decreased capmatinib exposure which may reduce its efficacy. Capmatinib is a CYP3A substrate and pexidartinib is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer decreased capmatinib exposure by 44%.
    Phenobarbital: (Major) Avoid coadministration of capmatinib and phenobarbital due to the risk of decreased capmatinib exposure, which may reduce its efficacy. Capmatinib is a CYP3A substrate and phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased capmatinib exposure by 67%.
    Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Avoid coadministration of capmatinib and phenobarbital due to the risk of decreased capmatinib exposure, which may reduce its efficacy. Capmatinib is a CYP3A substrate and phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased capmatinib exposure by 67%.
    Phenytoin: (Major) Avoid coadministration of capmatinib and phenytoin due to the risk of decreased capmatinib exposure, which may reduce its efficacy. Capmatinib is a CYP3A substrate and phenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased capmatinib exposure by 67%.
    Pioglitazone; Metformin: (Moderate) Monitor for an increased risk of metformin-related adverse reactions including lactic acidosis if coadministration with capmatinib is necessary; consider the benefits and risks of concomitant use. Metformin is a substrate of multidrug and toxin extrusion (MATE) and capmatinib is a MATE1 and MATE2K inhibitor. Coadministration may interfere with the renal elimination of metformin and increase metformin exposure.
    Posaconazole: (Moderate) Monitor for an increase in treatment-related adverse reactions if coadministration of capmatinib with posaconazole is necessary. Capmatinib is a CYP3A substrate and P-glycoprotein (P-gp) inhibitor. Posaconazole is a strong CYP3A4 inhibitor and a P-gp substrate. Coadministration with another strong CYP3A4 inhibitor increased capmatinib exposure by 42%. Inhibitors of P-gp may increase posaconazole exposure.
    Primidone: (Major) Avoid coadministration of capmatinib and primidone due to the risk of decreased capmatinib exposure, which may reduce its efficacy. Capmatinib is a CYP3A substrate and primidone is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased capmatinib exposure by 67%.
    Probenecid; Colchicine: (Major) Due to the risk for serious colchicine toxicity including multi-organ failure and death, avoid coadministration of colchicine and capmatinib in patients with normal renal and hepatic function unless the use of both agents is imperative. Coadministration is contraindicated in patients with renal or hepatic impairment because colchicine accumulation may be greater in these populations. Capmatinib can inhibit colchicine's metabolism via P-glycoprotein (P-gp), resulting in increased colchicine exposure. If coadministration in patients with normal renal and hepatic function cannot be avoided, adjust the dose of colchicine by either reducing the daily dose or the dosage frequency, and carefully monitor for colchicine toxicity. Specific dosage adjustment recommendations are available for the Colcrys product for patients who have taken capmatinib in the past 14 days or require concurrent use: for prophylaxis of gout flares, if the original dose is 0.6 mg twice daily, decrease to 0.3 mg once daily or if the original dose is 0.6 mg once daily, decrease to 0.3 mg once every other day; for treatment of gout flares, give 0.6 mg as a single dose, then 0.3 mg 1 hour later, and do not repeat for at least 3 days; for familial Mediterranean fever, do not exceed a 0.6 mg/day.
    Propranolol: (Moderate) Monitor patients for hypotension and bradycardia if coadministration of propranolol with capmatinib is necessary. Propranolol is partially metabolized by CYP1A2 and capmatinib is a weak CYP1A2 inhibitor. Concomitant use of CYP1A2 inhibitors may increase exposure to propranolol.
    Propranolol; Hydrochlorothiazide, HCTZ: (Moderate) Monitor patients for hypotension and bradycardia if coadministration of propranolol with capmatinib is necessary. Propranolol is partially metabolized by CYP1A2 and capmatinib is a weak CYP1A2 inhibitor. Concomitant use of CYP1A2 inhibitors may increase exposure to propranolol.
    Ranolazine: (Moderate) Monitor for an increase in ranolazine-related adverse reactions if coadministration with capmatinib is necessary; a dose adjustment of ranolazine may be necessary. Ranolazine is a P-glycoprotein (P-gp) substrate. Capmatinib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates.
    Rasagiline: (Moderate) Monitor for dopaminergic adverse effects during concurrent use of rasagiline and capmatinib. Coadministration may result in increased rasagiline concentrations. A dose reduction of rasagiline may be necessary. Rasagiline is primarily metabolized by CYP1A2; capmatinib is a weak CYP1A2 inhibitor. When administered with a strong CYP1A2 inhibitor, the AUC of rasagiline was increased by 83%.
    Relugolix: (Major) Avoid concomitant use of relugolix and oral capmatinib. Concomitant use may increase relugolix exposure and the risk of relugolix-related adverse effects. If concomitant use is unavoidable, administer capmatinib at least 6 hours after relugolix and monitor for adverse reactions. Relugolix is a P-glycoprotein (P-gp) substrate and capmatinib is a P-gp inhibitor.
    Relugolix; Estradiol; Norethindrone acetate: (Major) Avoid concomitant use of relugolix and oral capmatinib. Concomitant use may increase relugolix exposure and the risk of relugolix-related adverse effects. If concomitant use is unavoidable, administer capmatinib at least 6 hours after relugolix and monitor for adverse reactions. Relugolix is a P-glycoprotein (P-gp) substrate and capmatinib is a P-gp inhibitor.
    Ribociclib: (Moderate) Monitor for an increase in capmatinib-related adverse reactions if coadministration with ribociclib is necessary. Capmatinib is a CYP3A substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased capmatinib exposure by 42%.
    Ribociclib; Letrozole: (Moderate) Monitor for an increase in capmatinib-related adverse reactions if coadministration with ribociclib is necessary. Capmatinib is a CYP3A substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased capmatinib exposure by 42%.
    Rifabutin: (Major) Avoid coadministration of capmatinib and rifabutin due to the risk of decreased capmatinib exposure, which may reduce its efficacy. Capmatinib is a CYP3A substrate and rifabutin is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer decreased capmatinib exposure by 44%.
    Rifampin: (Major) Avoid coadministration of capmatinib and rifampin due to the risk of decreased capmatinib exposure, which may reduce its efficacy. Capmatinib is a CYP3A substrate and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin decreased capmatinib exposure by 67%.
    Rifapentine: (Major) Avoid coadministration of capmatinib and rifapentine due to the risk of decreased capmatinib exposure, which may reduce its efficacy. Capmatinib is a CYP3A substrate and rifapentine is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased capmatinib exposure by 67%.
    Rimegepant: (Major) Avoid a second dose of rimegepant within 48 hours if coadministered with capmatinib; concurrent use may increase rimegepant exposure. Rimegepant is a P-gp substrate and capmatinib is a P-gp inhibitor.
    Ritonavir: (Moderate) Monitor for an increase in capmatinib-related adverse reactions if coadministration with ritonavir is necessary. Capmatinib is a CYP3A substrate and ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased capmatinib exposure by 42%.
    Rosuvastatin: (Moderate) Monitor for an increase in rosuvastatin-related adverse reactions (i.e., myopathy/rhabdomyolysis) if coadministration with capmatinib is necessary. Rosuvastatin is a BCRP substrate and capmatinib is a BCRP inhibitor. Coadministration with capmatinib increased rosuvastatin exposure by 108%. If coadministration is unavoidable, consider a decrease the rosuvastatin dosage in accordance with the approved rosuvastatin prescribing information and the clinical goals for the patient.
    Rosuvastatin; Ezetimibe: (Moderate) Monitor for an increase in rosuvastatin-related adverse reactions (i.e., myopathy/rhabdomyolysis) if coadministration with capmatinib is necessary. Rosuvastatin is a BCRP substrate and capmatinib is a BCRP inhibitor. Coadministration with capmatinib increased rosuvastatin exposure by 108%. If coadministration is unavoidable, consider a decrease the rosuvastatin dosage in accordance with the approved rosuvastatin prescribing information and the clinical goals for the patient.
    Saquinavir: (Moderate) Monitor for an increase in treatment-related adverse reactions if coadministration of capmatinib with saquinavir is necessary. Capmatinib is a CYP3A substrate and P-glycoprotein (P-gp) inhibitor. Saquinavir is a strong CYP3A4 inhibitor and P-gp substrate. Coadministration with another strong CYP3A4 inhibitor increased capmatinib exposure by 42%. Inhibitors of P-gp may increase saquinavir exposure.
    SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
    Secobarbital: (Major) Avoid coadministration of capmatinib and secobarbital due to the risk of decreased capmatinib exposure, which may reduce its efficacy. Capmatinib is a CYP3A substrate and secobarbital is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer decreased capmatinib exposure by 44%.
    Silodosin: (Moderate) Monitor for an increase in silodosin-related adverse reactions if coadministration with capmatinib is necessary. Silodosin is a P-glycoprotein (P-gp) substrate and capmatinib is a P-gp inhibitor. Concomitant use may increase silodosin exposure.
    Sirolimus: (Major) Avoid coadministration of sirolimus with capmatinib as concurrent use may increase sirolimus exposure and risk of toxicity. Alternative agents with lesser interaction potential with sirolimus should be considered. Sirolimus is a P-gp substrate and capmatinib is a P-gp inhibitor.
    Sotorasib: (Major) Avoid coadministration of capmatinib and sotorasib due to the risk of decreased capmatinib exposure which may reduce its efficacy. Capmatinib is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer decreased capmatinib exposure by 44%.
    St. John's Wort, Hypericum perforatum: (Major) Avoid coadministration of capmatinib and St. John's Wort due to the risk of decreased capmatinib exposure, which may reduce its efficacy. Capmatinib is a CYP3A substrate and St. Johns Wort is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased capmatinib exposure by 67%.
    Sulfasalazine: (Moderate) Monitor for an increase in sulfasalazine-related adverse reactions if coadministration with capmatinib is necessary. Sulfasalazine is a BCRP substrate and capmatinib is a BCRP inhibitor.
    Talazoparib: (Major) Avoid coadministration of capmatinib with talazoparib if possible due to increased talazoparib exposure. If concomitant use is unavoidable, monitor for an increase in talazoparib-related adverse reactions. Talazoparib is a P-glycoprotein (P-gp) and BCRP substrate. Capmatinib is a P-gp and BCRP inhibitor. The effect of concomitant administration of BCRP inhibitors on the pharmacokinetics of talazoparib has not been studied; however, BCRP inhibitors may increase talazoparib exposure. Coadministration with other P-gp inhibitors increased talazoparib exposure by 8% to 45%.
    Telithromycin: (Moderate) Monitor for an increase in capmatinib-related adverse reactions if coadministration with telithromycin is necessary. Capmatinib is a CYP3A substrate and telithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased capmatinib exposure by 42%.
    Temsirolimus: (Moderate) Monitor for an increase in temsirolimus-related adverse reactions if coadministration with capmatinib is necessary due to the risk of increased temsirolimus exposure. Temsirolimus is a P-glycoprotein (P-gp) substrate and capmatinib is a P-gp inhibitor. Coadministration is likely to increase plasma concentrations of temsirolimus.
    Tenofovir Alafenamide: (Moderate) Coadministration of tenofovir alafenamide with capmatinib may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-glycoprotein (P-gp) and BCRP substrate and capmatinib is a P-gp and BCRP inhibitor.
    Tenofovir Alafenamide: (Moderate) Coadministration of tenofovir alafenamide with capmatinib may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-glycoprotein (P-gp) and BCRP substrate and capmatinib is a P-gp and BCRP inhibitor.
    Tenofovir, PMPA: (Moderate) Coadministration of tenofovir disoproxil fumarate with capmatinib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-glycoprotein (P-gp) and BCRP substrate and capmatinib is a P-gp and BCRP inhibitor.
    Theophylline, Aminophylline: (Moderate) Monitor theophylline concentrations and watch for an increase in aminophylline-related adverse reactions if coadministration with capmatinib is necessary; an aminophylline dose reduction may be necessary. Aminophylline is a CYP1A2 substrate with a narrow therapeutic index and capmatinib is a weak CYP1A2 inhibitor. (Moderate) Monitor theophylline concentrations and watch for an increase in theophylline-related adverse reactions if coadministration with capmatinib is necessary; a theophylline dose reduction may be necessary. Theophylline is a CYP1A2 substrate with a narrow therapeutic index and capmatinib is a weak CYP1A2 inhibitor.
    Thiopental: (Major) Avoid coadministration of capmatinib and thiopental due to the risk of decreased capmatinib exposure, which may reduce its efficacy. Capmatinib is a CYP3A substrate and thiopental is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer decreased capmatinib exposure by 44%.
    Ticagrelor: (Moderate) Monitor for increased bleeding if ticagrelor is coadministered with capmatinib as concurrent use may increase the exposure of ticagrelor. Ticagrelor is a P-gp substrate and capmatinib is a P-gp inhibitor.
    Tipranavir: (Moderate) Monitor for an increase in treatment-related adverse reactions if coadministration of capmatinib with tipranavir is necessary. Capmatinib is a CYP3A substrate and P-glycoprotein (P-gp) inhibitor. Tipranavir is a strong CYP3A4 inhibitor and a P-gp substrate. Coadministration with another strong CYP3A4 inhibitor increased capmatinib exposure by 42%. Inhibition of P-gp may increase tipranavir exposure.
    Tizanidine: (Major) Avoid concomitant use of tizanidine and capmatinib as increased tizanidine exposure may occur. If use together is necessary, initiate tizanidine at 2 mg and increase by 2 to 4 mg/day based on clinical response. Discontinue tizanidine if hypotension, bradycardia, or excessive drowsiness occurs. Tizanidine is a CYP1A2 substrate and capmatinib is a weak CYP1A2 inhibitor.
    Topotecan: (Major) Avoid coadministration of capmatinib with oral topotecan due to increased topotecan exposure; capmatinib may be administered with intravenous topotecan. Oral topotecan is a P-glycoprotein (P-gp) and BCRP substrate. Capmatinib is a P-gp and BCRP inhibitor. Coadministration increases the risk of topotecan-related adverse reactions.
    Tucatinib: (Moderate) Monitor for an increase in capmatinib-related adverse reactions if coadministration with tucatinib is necessary. Capmatinib is a CYP3A substrate and tucatinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased capmatinib exposure by 42%.
    Ubrogepant: (Major) Limit the initial and second dose of ubrogepant to 50 mg if coadministered with capmatinib. Concurrent use may increase ubrogepant exposure and the risk of adverse effects. Ubrogepant is a substrate of the BCRP and P-glycoprotein (P-gp) drug transporters; capmatinib is a BCRP and P-gp inhibitor.
    Venetoclax: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with capmatinib due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of capmatinib. Capmatinib is a P-glycoprotein (P-gp) inhibitor; venetoclax is a P-gp substrate. Coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study.
    Vincristine Liposomal: (Moderate) Monitor for vincristine-related adverse reactions if coadministration of capmatinib is necessary as concurrent use may increase vincristine exposure. Vincristine is a P-glycoprotein (P-gp) substrate and capmatinib is a P-gp inhibitor.
    Vincristine: (Moderate) Monitor for vincristine-related adverse reactions if coadministration of capmatinib is necessary as concurrent use may increase vincristine exposure. Vincristine is a P-glycoprotein (P-gp) substrate and capmatinib is a P-gp inhibitor.
    Voriconazole: (Moderate) Monitor for an increase in capmatinib-related adverse reactions if coadministration with voriconazole is necessary. Capmatinib is a CYP3A substrate and voriconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased capmatinib exposure by 42%.
    Warfarin: (Moderate) Closely monitor the INR if coadministration of warfarin with capmatinib is necessary as concurrent use may increase the exposure of warfarin, leading to increased bleeding risk. Capmatinib is a CYP1A2 inhibitor and the R-enantiomer of warfarin is a CYP1A2 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.

    PREGNANCY AND LACTATION

    Pregnancy

    Pregnancy should be avoided by females of reproductive potential during capmatinib treatment and for at least 1 week after the last dose. Although there are no adequately controlled studies in pregnant women, capmatinib can cause fetal harm or death when administered during pregnancy based on its mechanism of action and animal studies. Women who are pregnant or who become pregnant while receiving capmatinib should be apprised of the potential hazard to the fetus. In rats, maternal toxicity (reduced weight gain and food consumption) occurred at approximately 1.4 times the human exposure at the recommended dose based on AUC. There were no maternal effects in rabbits at exposures of approximately 1.5 times the human exposure at the recommended dose based on AUC. At exposures of approximately 0.6 times the human exposure at the recommended dose based on AUC in rats, fetal effects included reduced weight, irregular/incomplete ossification, and increased fetal malformations (e.g., abnormal flexure/inward malrotation of hindpaws/forepaws, thinness of forelimbs, lack of or reduced flexion at the humerus/ulna joints, and narrowed or small tongue). These fetal effects were seen at much lower exposures in rabbits (approximately 0.016 times the human exposure based on AUC at the recommended dose).

    Counsel patients about the reproductive risk and contraception requirements during capmatinib treatment. Capmatinib can be teratogenic if taken by the mother during pregnancy. Females of reproductive potential should avoid pregnancy and use effective contraception during and for at least 1 week after treatment with capmatinib. Due to the risk of male-mediated teratogenicity, males with female partners of reproductive potential should also use effective contraception during treatment and for at least 1 week after the last dose. Females of reproductive potential should undergo pregnancy testing prior to initiation of capmatinib. Women who become pregnant while receiving capmatinib should be apprised of the potential hazard to the fetus.

    MECHANISM OF ACTION

    Capmatinib is a kinase inhibitor that targets MET, including the mutant variant produced by exon 14 skipping. MET exon 14 skipping results in a protein with a missing regulatory domain that reduces its negative regulation, leading to increased downstream MET signaling. Capmatinib inhibited cancer cell growth driven by a mutant MET variant lacking exon 14 at clinically achievable concentrations and demonstrated anti-tumor activity in murine tumor xenograft models derived from human lung tumors with either a mutation leading to MET exon 14 skipping or MET amplification. Capmatinib inhibited the phosphorylation of MET triggered by binding of hepatocyte growth factor or by MET amplification, as well as MET-mediated phosphorylation of downstream signaling proteins and proliferation and survival of MET-dependent cancer cells.

    PHARMACOKINETICS

    Capmatinib is administered orally. It is 96% bound to plasma proteins, independent of concentration. The apparent mean volume of distribution at steady-state is 164 liters. The blood-to-plasma ratio was 1.5, but decreased at higher concentrations to 0.9. The effective elimination half-life of capmatinib is 6.5 hours, and the mean steady-state apparent clearance is 24 liters/hour (CV, 82%). After a single oral radiolabeled dose of capmatinib to healthy volunteers, 78% of the dose was recovered in feces (unchanged, 42%) and 22% was recovered in the urine; the amount of unchanged drug in the urine was minimal.
     
    Affected cytochrome P450 (CYP450) isoenzymes and drug transporters: CYP1A2, CYP3A, P-glycoprotein (P-gp), BCRP, MATE1, MATE2K
    Capmatinib is primarily metabolized by CYP3A4 and aldehyde oxidase; in vitro, it is also a P-gp substrate. Capmatinib inhibits CYP1A2, P-gp, and BCRP in vivo; in vitro, it also reversibly inhibits MATE1 and MATE2K.

    Oral Route

    Capmatinib exposure (AUC and Cmax) increased approximately proportionally over a dose range of 200 mg to 400 mg. Capmatinib reached steady-state by day 3 following twice-daily dosing, with a mean accumulation ratio of 1.5 (CV, 41%). The exposure-response relationship and time course of pharmacodynamic response are unknown. After administration of capmatinib 400 mg to patients with cancer, peak plasma concentrations (Cmax) were reached in approximately 1 to 2 hours (Tmax). The absorption of capmatinib after oral administration is estimated to be greater than 70%).
     
    The AUC of capmatinib increased by 46% when taken with a high-fat meal (approximately 1,000 calories, 50% fat) compared to fasting conditions in healthy subjects; there was no change in Cmax. A low-fat meal (approximately 300 calories, 20% fat) did not have a clinically meaningful effect on capmatinib exposure. In cancer patients, the AUC of capmatinib was similar after administration with food and under fasting conditions. Administration with a proton pump inhibitor decreased capmatinib exposure by 25% and decreased the Cmax by 38%.